Huntington's disease is caused by expansion of a polyglutamine tract in the protein huntingtin. Polyglutamine expansion in other proteins can also cause disease: for example, dentatorubral and pallidoluysian atrophy (DRPLA) is related to a polyglutamine expansion in atrophin-1. In Huntington's disease, huntingtin aggregates form in neurons, but the relationship between aggregate formation and neuron death is unclear.

Nucifora et al. looked at the effects of mutant huntingtin and atrophin-1 on gene transcription mediated by CREB-binding protein (CBP). CREB and CBP mediate the expression of neuronal survival factors, including brain-derived neurotrophic factor (BDNF), and the expression of BDNF is reduced in Huntington's disease. As CBP contains a short polyglutamine tract, Nucifora et al., following earlier suggestions from Perutz, Housman, Fischbeck and others, proposed that the expanded polyglutamine tract in huntingtin might interact with this part of the protein. Indeed, Nucifora et al. found that when CBP and mutant huntingtin were expressed together in neuroblastoma cells, CBP was redistributed away from the nucleus into huntingtin aggregates. By contrast, a modified form of CBP without the polyglutamine tract was not redistributed.

Co-immunoprecipitation experiments showed that CBP and expanded huntingtin interact directly. But how does this interaction cause neuronal toxicity? Nucifora et al. carried out transcription assays on primary cortical neurons and found that mutant huntingtin or atrophin-1 inhibited CBP-mediated gene transcription. This effect required abnormal interactions that involve the polyglutamine segments in the proteins, as the use of either normal huntingtin or CBP lacking the polyglutamine tract prevented the inhibition of transcription. Finally, the researchers showed that overexpression of CBP could prevent the death of cells containing the amino-terminal fragment of mutant huntingtin or atrophin-1.

These results indicate that at least some of the neurotoxic effects of the mutated forms of huntingtin and atrophin-1 probably result from their interaction with CBP, which might inhibit the expression of survival factors such as BDNF. In addition, mutant huntingtin might also interact with other proteins that contain glutamine repeats. So, the interaction between expanded polyglutamine tracts in huntingtin and short glutamine repeats in other proteins might represent a unifying mechanism for polyglutamine toxicity, and a potential target for therapy in diseases such as Huntington's disease and DRPLA.